Yue Zhao

ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription

AbstractAbsent, small or homeotic 2‐like protein (ASH2L) is a core component of a multimeric histone methyltransferase complex that is involved in the maintenance of active transcription, participating in several cancers, however the biological function and molecular mechanism of ASH2L in endometrial cancer (ECa) are largely unknown. Endometrial cancer is a common malignant tumor in women and the incidence of this cancer is on the rise. Estrogen‐ERα signaling, as an oncogenic pathway, plays a crucial role in endometrial carcinogenesis. Therefore, further exploration of the molecular mechanisms around ERα‐mediated gene transcription in ECa would be helpful to the understanding of tumor development and to finding a new therapeutic target for ECa. Here, our study demonstrated that ASH2L was highly expressed in ECa samples, and higher expression of ASH2L was positively correlated with a poor prognosis. Moreover, we identified that ASH2L associated with ERα and that knockdown of ASH2L resulted in decreased expression of a subset of the estrogen‐induced target genes, including paired box 2 (PAX2), an oncogenic gene in ECa. ASH2L was recruited to cis‐regulatory elements in PAX2, thereby altering histone H3K4me3 and H3K27me3 levels, to enhance ERα‐mediated transactivation. Finally, depletion of ASH2L suppressed endometrial cancer cell proliferation and migration. Our findings suggest that ASH2L participates in the promotion of ECa progression, if not totally at least partially, via upregulation of PAX2 transcription.

Deep Pathway Analysis V2.0: A Pathway Analysis Framework Incorporating Multi-Dimensional Omics Data

Pathway analysis is essential in cancer research particularly when scientists attempt to derive interpretation from genome-wide high-throughput experimental data. If pathway information is organized into a network topology, its use in interpreting omics data can become very powerful. In this paper, we propose a topology-based pathway analysis method, called DPA V2.0, which can combine multiple heterogeneous omics data types in its analysis. In this method, each pathway route is encoded as a Bayesian network which is initialized with a sequence of conditional probabilities specifically designed to encode directionality of regulatory relationships defined in the pathway. Unlike other topology-based pathway tools, DPA is capable of identifying pathway routes as representatives of perturbed regulatory signals. We demonstrate the effectiveness of our model by applying it to two well-established TCGA data sets, namely, breast cancer study (BRCA) and ovarian cancer study (OV). The analysis combines mRNA-seq, mutation, copy number variation, and phosphorylation data publicly available for both TCGA data sets. We performed survival analysis and patient subtype analysis and the analysis outcomes revealed the anticipated strengths of our model. We hope that the availability of our model encourages wet lab scientists to generate extra data sets to reap the benefits of using multiple data types in pathway analysis. The majority of pathways distinguished can be confirmed by biological literature. Moreover, the proportion of correctly indentified pathways is 10 percent higher than previous work where only mRNA-seq and mutation data is incorporated for breast cancer patients. Consequently, such an in-depth pathway analysis incorporating more diverse data can give rise to the accuracy of perturbed pathway detection.